AmyriAD Therapeutics is looking to evaluate its lead Alzheimer’s disease small molecule candidate AD-101 in three upcoming Phase III studies, CEO Sharon Rogers, PhD, told Clinical Trials Arena.

The Los Angeles, California-based company aims to expand the patient population for its treatment by designing the clinical trials to include patients with mild to severe Alzheimer’s instead of mild to moderate or moderate to severe disease, explains Rogers. Evaluating patients at the highest end of the mild disease group is “very tough” while measuring drug effects because even though evaluation scales like the mini-mental state examination (MMSE) and others, can detect deficiencies, they are not sensitive enough to quantify them, she elaborates.

Of the Phase III studies, two—a US trial and another in Europe and Southeast Asia regions— will be designed as adequate and well-controlled (AWC) studies for safety and efficacy that will enrol 500 patients each. Patients in the trials will be enrolled into two equal arms and administered treatment over a 24-week period. Patients on one arm will receive a single dose of the AD-101/Aricept (donepezil) combination treatment while the other group will be given a placebo/Aricept combination.

AD-101 is a once-daily low-voltage-gated T-type calcium channel modulator that increases the release of endogenous acetylcholine. The AD-101/Aricept combination is designed to promote the release of neurotransmitter acetylcholine and preserve it. As per the data from the randomised, double blind, placebo-controlled Phase II proof-of-concept study shared by the company at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, there was additive efficacy in symptom relief when AD-101 was added to a 10 mg daily dose of Aricept.

The Phase III endpoints must demonstrate that a drug improves cognition, a core symptom of the disease, and this should be done using the ADAS-Cog scale, said Rogers. ADAS-Cog is “the gold standard tool” for cognition as it evaluates every category of cognition unlike other tools which are slanted toward language deficits and not as robust at measuring other cognitive domains, she adds.

Another important Phase III endpoint is the independent global function evaluated using AGS-CGIC, which was used in the company’s positive Phase II study and will be used in the upcoming Phase III trials too, said Rogers. AmyriAD will likely use clinical dementia rating (CDR) or the CDR SOB evaluation measures as secondary global endpoints.

Patients must have measurable dementia for diagnosis and inclusion in a clinical trial, said Rogers. As such, AmyriAD will use an MMSE score of 10–22 to include patients with mild to moderately severe Alzheimer’s disease. Patients in this range are functional enough to provide consent and cooperate with the study, which reduces operational complications of a study, Rogers adds.

The US trial is slotted to commence in Q3 2024, and the Europe and Southeast Asia trials are tentatively planned for Q1 2025, said Rogers. Once patients complete participation in the AWC studies, an open label Phase III extension study will be pursued to characterise long term safety and efficacy of the treatment, said Rogers.